Prions — pathogens that are lethal to humans and other animals — arethought to be conformational isomers of the cellular prion protein.Their unique biology, and the potential for a wider pathobiologicalsignificance of prion-like mechanisms, has motivated much research intounderstanding prion neurodegeneration. Moreover, concerns that extensivedietary exposure to bovine spongiform encephalopathy (BSE) prions mighthave infected many individuals — who might eventually develop its humancounterpart, variant Creutzfeldt–Jakob disease (vCJD) — has focused muchinterest on therapeutics. The challenge of interrupting this aggressive,diffuse and uniformly fatal neurodegenerative process is daunting.However, the recent finding that the onset of clinical disease inestablished neuroinvasive prion infection in a mouse model can be haltedand early pathology reversed is a source for considerable optimism. Atherapeutic focus on the cellular prion protein, rather than prionsthemselves, which might not be directly neurotoxic, is suggested.

Summary

* Prion diseases, or transmissible spongiform encephalopathies, arefatal neurodegenerative conditions that affect humans and otheranimals, and are transmissible within or between mammalianspecies. The recognition in 1996 of a new human prion disease —variant CreutzfeldtJakob disease (vCJD) — and the experimentalconfirmation that it is caused by bovine spongiform encephalopathy(BSE)-like prions derived from infected beef products have led tofears of a human epidemic.* Prion diseases are all associated with the accumulation in thebrain of an abnormal, partially protease-resistant, isoform ofhost-encoded prion protein (PrP). The disease-related isoform(PrPSc) is derived from the normal cellular isoform PrPC by apost-translational process that involves conformational change andaggregation. Many studies support the 'protein-only' hypothesis ofprion propagation, according to which an abnormal PrP isoform isthe principal, and possibly the sole, constituent of thetransmissible agent or prion. Therefore, PrPSc is thought to actas a conformational template, recruiting PrPC to form further PrPSc.* However, the cause of neuronal death in prion disease remainsunclear. The assumption that neurodegeneration follows from directtoxicity of PrPSc and/or prions has been increasingly challenged.Evidence against the direct toxicity of PrPSc is discussed, withparticular reference to the occurrence of sub-clinical forms ofprion infection, in which high levels of PrPSc accumulate in theabsence of neurotoxicity or clinical symptoms, as well as the morerecent demonstration that switching off PrPC expression in micewith neuroinvasive prion disease results in the reversal of earlyspongiform degeneration and long-term survival of animals despiteongoing non-neuronal PrPSc production.* Other potential mechanisms of neurotoxicity in prion diseases arepresented, including possible roles for PrPC in cell survival andcell death signalling pathways and the potential toxicity ofaberrant PrPC processing and trafficking in neurons.* The concept of the generation of neurotoxic forms of PrP,designated 'PrPL' (PrP lethal), during prion replication, whichmight involve soluble oligomers of misfolded PrP, is emphasized.The rationale for focussing on therapeutic strategies that targetnormal PrPC rather than PrPSc itself, where stabilizing the nativeform will prevent the generation of toxic intermediates, isexplained.The balance between the production and clearance of PrPL(and PrPSc) in prion infection in determining ultimateneurotoxicity is discussed, with particular relevance fortherapeutic intervention.* Other therapeutic strategies, including targeting PrPSc andimmunotherapeutic modulation, are considered, as well as potentialfuture strategies, such as gene silencing by RNA interference and,ultimately, stem cell therapy for the repair of damaged tissue.* Consideration is given to human therapeutic studies and the needfor advances in the early diagnosis of prion infection.